Genetics of Alcohol Dependence: A Review of Clinical Studies

Abstract

Background/Aims: Alcohol dependence is a common severe psychiatric disorder with a multifactorial etiology. Since the completion of the human genome project and with the increased availability of high-throughput genotyping, multiple genetic risk factors for substance-related disorders, including alcohol dependence, have been identified, but not all results could be replicated. Methods: We systematically review the clinical literature on genetic risk factors for alcohol dependence and alcohol-related phenotypes, including candidate gene-based studies, linkage studies and genome-wide association studies (GWAS). Results: Irrespectively of the methodology employed, the most robust findings regarding genetic risk factors for alcohol dependence concern genetic variations that affect alcohol metabolism. GWAS confirm the importance of the alcohol dehydrogenase gene cluster on chromosome 4 in the genetic risk for alcohol dependence with multiple variants that exert a small, but cumulative influence. A single variant with strong influence on individual risk is the aldehyde dehydrogenase 2 ALDHD2*2 variant common in Asian populations. Other robust associations have been found with previously uncharacterized genes like KIAA0040, and such observations can lead to the identification of thus far unknown signaling pathways. Converging evidence also points to a role of glutamatergic, dopaminergic and serotonergic neurotransmitter signaling in the risk for alcohol dependence, but effects are small, and gene-environment interactions further increase the complexity. Conclusion: With few exceptions like ALDH2*2, the contribution of individual genetic variants to the risk for alcohol-related disorders is small. However, the concentration of risk variants within neurotransmitter signaling pathways may help to deepen our understanding of the underlying pathophysiology and thereby contribute to develop novel therapeutic strategies.

Are Alcohol Trajectories a Useful Way of Identifying At-Risk Youth? A Multiwave Longitudinal-Epidemiologic Study

“…With the exception of an aldehyde dehydrogenase variant ( ALDH2*2 ) in East Asian populations, alleles of large effect have not been identified. 37 Although a number of common alleles have been identified through genome-wide association methods, these are of very small effect. 38 Thus, like other complex diseases such as diabetes 39 and traits such as height, 40 alcohol use is characterized by polygenic inheritance.…”

Behavioral and Neural Manifestations of Reward Memory in Carriers of Low-Expressing versus High-Expressing Genetic Variants of the Dopamine D2 Receptor

“…While the results of genetic association studies are thus far inconclusive with respect to actual disease risk (Samochowiec et al, 2014), studies of intermediate phenotypes have successfully demonstrated effects of genetic variability in the dopamine system on human motivational and cognitive processing (Meyer-Lindenberg and Weinberger, 2006; Yacubian et al, 2007; Richter et al, 2013, 2014; Wittmann et al, 2013). Most neurobiological investigations of addiction in humans and animals have highlighted the role of dysfunctional dopaminergic transmission in the ventral striatum/nucleus accumbens (NAcc) and reduced striatal D2 receptor availability (Kienast and Heinz, 2006; Everitt, 2014), but some authors have also pointed out the role of the hippocampus, which is critically involved in the formation of long-term memories (Robbins and Everitt, 2002; Robbins et al, 2008).…”

Genetic variability in tryptophan hydroxylase 2 gene in alcohol dependence and alcohol-related psychopathological symptoms

“…Several genes involved in alcohol metabolism, as well as genes involved in serotonergic, GABA-ergic, opioid, cannabinoid, dopaminergic and cholinergic transmission, were proposed to contribute to this heritability [5,6,8,26]. Recently published review of candidate gene-based studies, linkage studies and genome-wide association studies pointed out a limited role of individual genetic variants in the risk for alcohol dependence, although single risk variants within neurotransmitter signalling pathways may help to deepen the understanding of the underlying pathophysiology of alcohol dependence [21]. Serotonin (5-HT) has been shown to regulate alcohol consumption in both animals and humans and is considered to be involved in many aspects of alcohol consumption, abuse and dependence [10].…”